Chronic unremitting pain can lead to the abuse of narcotic opioid analgesics or provide a significant challenge to individuals seeking recovery from addiction. Most research on the analgesic mechanisms of opioids have focused on models of cutaneous pain, often conducted in animals. Comparatively little is known about opioid actions on muscle pain, and almost no biochemical pharmacology studies have been conducted in humans suffering from muscle pain. This gap in knowledge is compounded by the fact that musculoskeletal pain represents one of the most common forms of chronic pain. This proposal consists of a series of controlled clinical studies which will determine the peripheral opioid modulation of selected biochemical markers of certain sensory neurons and sympathetic fibers, perceived pain levels and mechanical hyperalgesia thresholds in normal subjects as compared to acute and chronic muscle pain patients. Specifically, the proposed studies will address the following aims: 1. Determine the temporal development of exercise-induced mechanical hyperalgesia, pain and local tissue levels of iSP and NE (using implanted microdialysis probes) in control subjects, acute muscle pain patients (pain of less than six months duration) and chronic pain patients (pain of six months or more duration). 2. Determine whether opioids activate peripheral mechanisms to alter the development of mechanical hyperalgesia and local release of iSP and NE using a computer-feedback program to elicit controlled muscle hyperalgesia in these three patient populations. As compared to healthy control subjects, it is hypothesized that the acute and chronic pain patient populations will demonstrate reduced responsiveness to opioid effects on perceptual changes to controlled muscle hyperalgesia. 3. Determine the role of certain sensory neurons, and whether peripheral opioid actions are mediated by altered sensory neuron activity, in the development of muscle hyperalgesia. It is hypothesized that the acute and chronic pain patient populations will demonstrate reduced responsiveness to opioid effects on perceptual and local 5P-induced changes to controlled muscle hyperalgesia. 4. Determine the role of certain sympathetic fiber terminals, and whether peripheral opioid actions are mediated by altered sympathetic fiber activity, in the development of muscle hyperalgesia. It is hypothesized that the acute and chronic pain patient populations will demonstrate reduced responsiveness to opioid effects on perceptual and local adrenergic agonist-induced changes to controlled muscle hyperalgesia. Collectively, these studies will: 1) determine peripheral actions of opioids for altering biochemical and perceptual (i.e., analgesia) indices of muscle hyperalgesla; and 2) evaluate whether the chronic pain patient is vulnerable to opioid abuse through reduced peripheral efficacy of opioids.